This is a renewal application from faculty members at the University of Utah for support of an Acute Lung Injury SCOR. The broad objective of the Utah SCOR is to systematically dissect the cellular and molecular complexity of the Acute Respiratory Distress Syndrome (ARDS), identifying specific facets that can ultimately be manipulated to prevent and/or effectively treat this devastating disorder. The thematic hypothesis being pursued in this SCOR proposal is that ARDS results from dysregulated cell- cell interactions that initiate and/or amplify inflammatory injury to the alveolar capillary membrane. In this hypothesis, endothelial cells are critically involved in initiating the dysregulated inflammation. The hypothesis will be addressed by a multi-disciplinary research program featuring a combination of interrelated clinical and basic investigations designed to generate new knowledge that will improve our understanding of the pathobiochemistry of ARDS, in treatment, and prevention. In the SCOR, productive established investigators with excellent track records of interaction have combined to direct five projects and four cores. Each project addresses novel mechanisms and is oriented around the central theme. Each project is supported by preliminary data that inspire confidence as to the importance and feasibility of the proposed studies. By orienting the proposal around the endothelial cell, and the molecular events that influence cell-cell interactions, all five projects interact and intrinsically reinforce each other in almost every phase of their studies. The "intellectual structure" of the SCOR is as follows: Project 1: Novel Inflammatory Responses of Injured Endothelium investigates the mechanisms by which clinically relevant novel endotoxins produce lung injury focusing particularly on the interactions of these agents with the endothelial cell. The next project: Acute Lung Injury: The Role of Vascular NAD(P)H Oxidase investigates the role by which oxidants generated by endothelial cells cause cellular dysfunction. The next project: Dysregulated Expression in Signaling Molecules and Project 4: The Role of Endothelin in Acute Lung Injury investigate the mechanisms by which pro- inflammatory cytokines elaborated from endothelial cells cause inflammation that results in lung injury. Project 5: Regulation of Inflammatory Lipids in Acute Lung Injury explores the mechanisms of inflammation control. Each of four Cores provides support for all five projects. Each project investigates the mechanisms of dysregulated inflammation not only in model systems but also in humans. Each project investigates the mechanisms of dysregulated inflammation not only in model systems but also in humans. The proposal offers an established research program, proven multi- disciplinary collaborative interactions, and a rich environment for productive basic and clinical research.